The examination of immunoglobulin (Ig) genes has revealed an ordered hierarchy in which heavy chain genes rearrange before light and Kappa generally rearranges before Lambda. Part of this ordered process is a deletional loss of Kappa gene segment within Lambda producing B cells, and we have identified a new recombinatorial element that uniformly mediates this Kappa loss. The "non-T, non-B" acute lymphoblastic leukemias were shown to be a developmental series of B-cell precursors with a coordinate sequence of cell surface antigen expression and Ig gene rearrangements. These leukemias represent landmarks enabling the identification of genes that are transcriptionally activated during the early stages of B cells. As cells of non-B lineage retain germline light and usually heavy chain genes, the configuration of Ig genes provides a molecular lineage marker. Ig gene analysis definitively established hairy cell leukemia as a genotypic B-cell, but one which expressed receptors for interleukin-2. Furthermore, Ig gene rearrangements have served as sensitive and specific markers capable of identifying minority populations of clonal B cells in tissues of mixed cellularity; these tumor-specific molecular markers have been of great use in early detection, classification, and following the natural history of lymphoid neoplasms. B-cell differentiation was also inducible with phorbol esters and allowed elucidation of the role of c-Myc in maturational arrest. Frequently Ig gene rearrangements are intermediate or aberrant preventing Ig production while other molecular errors account for the truncated proteins of heavy chain disease (HCD). A case of Mu HCD proved to have an RNA splicing error responsible for its small heavy chain without light chain; whereas, in contrast a Gamma HCD had a DNA deletional rearrangement. Chromosomal translocations can also rearrange in Ig gene loci, and we are utilizing such a heavy chain rearrangement to identify a new cancer related gene being introduced from chromosome 18 in certain lymphomas.